The last decade of cardiac surgery has witnessed significant strides towards better understanding and better management of previously lethal cardiac pathology.
Two important manifestations stand out in particular. First, the decade has witnessed a remarkable improvement in techniques for preserving the myocardium (heart muscle) from irreversible damage, coupled with a widening choice of sophisticated ways to correct myocardial ischemia. Second, practitioners generally recognize new conditions such as myocardial stunning and hibemation where the injured myocardium is in a state of "suspended animation," closely resembling total necrosis but very different in practice since it retains enough viability to allow for function retrieval by modem techniques. Varying intermediate degrees of the above situations have also been identified.
Faced with the recognition of this widening variety of ischemic clinical pictures with variable degrees of retained viability, and armed with the knowledge that several conditions previously considered hopeless can now be salvaged if appropriately recognized as viable, cardiologists and cardiac surgeons are increasingly aware of the need to optimize selection from their ever-widening choice of techniques in a way that matches the particular clinical situation.
By necessity, such a goal would depend on our ability to assess viability in an injured myocardium as accurately as possible.
The regional nature of coronary occlusive disease produces a need for a non-invasive means of assessing regional oxidative metabolism in cardiac patients. To those familiar with this art, there is no method presently known of accurately and quickly measuring regional tissue oxygen availability and utilization in human beings. Standard clinical indicators are insensitive to the non-uniform drop-out of myocardial perfusion-metabolism units associated with coronary insufficiency. Radionuclide and angiographic methods permit the evaluation of myocardial perfusion and ventricular wall motion, but the metabolic state of the myocardium cannot be reliably predicted with these methods, particularly in patients with marginal perfusion and/or abnormal ventricular wall motion.
Current methods for assessing myocardial viability each have significant shortcomings. (1) The "educated clinical guess" is based on EKG readings and cardiac enzyme measurements, angiographic evidence of ventricular contractility and collateral circulation. This provides a sound general assessment but lacks the accuracy needed to fine-tune the clinical and surgical management. (2) Thallium 201 perfusion/redistribution studies are used to outline regions of cardiac ischemia or scarring. Unfortunately, these studies are time consuming, cannot be applied to acute conditions, and have been proved inaccurate in diagnosing sear in 32% of cases (as shown by PET scanning). (3) Position emission tomography (PET) scanning utilizes a radioactive metabolic tracer, usually a glucose analogue, to follow tracer uptake by viable myoeardial cells, as detected by positron emission. This method is the most accurate detector of viable myocardium so far but it is complicated and quite expensive, and is not practical in the acute phase so it is only used in a few academic centers. (4) Biopsy specimens may show metabolic and structural signs of irreversible damage such as the adenosine triphosphate (ATP) intracellular levels and triphenyltetrazolium chloride (TTC) vital staining (or lack thereof). Although these tests were previously accepted as reliable, they have now been found to be inaccurate. R. J. Barnard, et al., "Studes of Controlled Reperfusion After Ischemia - III. Histochemical studies: Inability of triphenyltetrazolium chloride non-staining to define tissue necrosis," J. Thorac. Cardiovasc. Surg. 92:502-12 (1986). For example, a recently neefolio cell or stunned myocardium will show similar low levels of ATP yet the stunned myocardium could be saved if recognized and treated promptly. Of the presently available methods, PET scanning comes closest to fulfilling the need for assessing viability. However, it is expensive, often impractical and still does not help in the acute phase.
Some methods of measuring myocardial metabolism such as Magnetic Resonance Imaging/Spectroscopy and Positron Emission Tomography are costly and require cumbersome equipment (magnets and cyclotrons) which are not compatible with the cardiac catheterization laboratory setting found in most hospitals and/or clinics. The test procedures also require considerable time to carry out, and a patient suffering an acute heart attack generally cannot be evaluated by these methods with enough time left to implement a corrective procedure.
The capacity to rapidly discern the metabolic state of the beating human heart, particularly within abnormally contracting myocardial segments, would beneficially affect clinical decisions regarding the need for therapeutic interventions such as blood clot dissolving agents, balloon angioplasty, and coronary artery bypass grafting.
Several researchers have worked on steady state evaluations using a variety of spectrophotometric methods. A good review of the prior art spectrophotometric methods for measuring circulatory and respiratory functions, arterial blood oxygenation and blood samples is set forth in U.S. Pat. Nos. 4,223,680 and 4,281,645 to Jobsis. The application of differential spectroscopy using near infrared (NIR) light in blood perfused body organs was advanced by Jobsis as described in detail in the aforementioned patents.
Jobsis emphasized in these patents that near infrared (NIR) light must span a relatively long path (e.g. several centimeters) in length in order for his invention to work. The long pathlength is significant in that it allows the light photons to travel deeply into the tissue of interest so that the received optical signal will contain information from a substantial volume of tissue. Also, the longer path length minimizes the light-scattering effects of structures which are superficial to the region of interest. Since, as shown in FIG. 2 of U.S. Pat. No. 4,223,680, the back-scattered light from superficial structures may not contain metabolic information of interest, and may obscure detection of the desired metabolic information, a method was sought by Jobsis to minimize this biophysical effect. Accordingly, both Jobsis patents teach that the near infrared (NIR) light must be transmitted to the test organ (in situ) and then the radiation intensity must be detected and measured at a point spaced apart from the point of light entry. As indicated in FIG. 1 and FIG. 2 of U.S. Pat. No. 4,223,680, the physical distance between entrance and exit of near infrared (NIR) light is specified to be several centimeters.
Others follow the Jobsis teaching that the light detector fiber bundle must be spaced apart from the light source fiber bundle to minimize light scattering from superficial tissue regions. Parsons et al., in U.S. Pat. Nos. 5,161,531 and 5,127,409 disclose bundles spaced apart even if the light source fiber bundle and light detector fiber bundle are oriented parallel to each other as suggested by Abe in U.S. Pat. No. 4,513,751. Simply transmitting near infrared (NIR) light down one optical fiber and receiving the reflected light with a second optical fiber which is parallel and immediately adjacent to the transmitting fiber, as proposed by Abe for visible light wavelengths, will not permit the desired accurate near infrared (NIR) measurement of oxidative metabolism within a substantial tissue volume.
Summarily, it is highly desirable for intravascular application of a red to near-infrared (NIR) light sending and receiving device that a single scope containing both the transmitting and receiving optical fibers be used to acquire optical information from an endocardial site. The introduction of two separate send and receive scopes by a percutaneous, intravascular approach to the endocardium would be hampered by motion artifact of the beating myocardial wall and the instability of the optical alignment of the two scopes relative to the tissue region of interest. Parsons et al. sought to overcome the shortcomings of the prior art as disclosed in the Jobsis and Abe patents by using a steerable fiber optic device to deliver and receive near infrared (NIR) light through a single small-diameter scope (less than 3.3 mm in diameter) positioned at the endocardial surface by means of a percutaneous intravaseular approach which is applicable in a standard clinical catheterization laboratory. The procedure using the Parsons et al. device can be done as part of a routine diagnostic catheterization study, and permits the steady-state measurement of regional myocardial oxygenation from within the beating heart.
A variety of products and devices that enter the myocardium are currently used to evaluate tissue status.
______________________________________ Products Primary Users ______________________________________ Cardiac catheters Cardiologists Electrophysiology pacing wires Cardiologists, Surgeons Biopsy device Surgeons Hemo-pump Surgeons Intravascular ultrasound Cardiologists Atherectomy device/catheter Cardiologists Laser fibers Cardiologists Coronary angioscope Cardiologists ______________________________________
Many of these procedures are performed on a daily basis in most acute care centers with cardiac catheterization being the most frequent intervention. No valvular damage is caused by any of these devices as they cross the valves. Stenotic (narrowed) valves in certain diseases may not allow passage of the catheter. Prosthetic valves do not allow passage of the catheter.
Prospect For PET, NMR, and Ultrasound Backscatter Technology
Positron emission tomography (PET) has many limitations, many of which are anticipated to be insurmountable over the next 3-5 years. PET is a large expensive device. It is therefore rarely available even in large medical centers. Miniaturization of the technology and reduction of its cost is most unlikely over the next five years. A good example of this is Nuclear Magnetic Resonance (NMR) technology, also known as magnetic resonance imaging (MRI). NMR is a very old technology, originally developed over 40 years ago. To date, MRI imaging machines are very large, very expensive and only sometime available even in large medical centers. Similarly, computerized axial tomography machines (CT or CAT scanners), although more widely available now, are still very large, expensive and require specific building and structural arrangement. Many hospitals rely on leasing mobile scanners or simply refer studies to outside service providers. Each of these difficulties means the analytical equipment is relatively less available but only limited time is available for evaluating viable tissue after an ischemic attack. This time is optimally one to two hours, although useful recovery is possible in some cases after several hours.
In addition to these limitations, PET scanners cannot detect myocardial damage in the acute state of myocardial infarction. Furthermore, it is very unlikely to place a patient suffering an acute myocardial infarction inside a large scanner in the radiology department for a prolonged period of time while images are being collected. More appropriately, such a patient should be in the cardiac catheterization laboratory where the heart can be eatheterized, myocardial wall viability assessed with the tissue viability monitor, and appropriate interventions performed.
A further serious limitation of the PET scanner is the need for a facility to generate radioactive isotope. Such facilities are large, expensive, and not usually present in many large cities. The isotope half-life is very short. The remoteness of the isotope generating facility from most cities and medical centers and the short half-life of the isotope require the special ordering of the isotope acutely for each selected case and the use of airlines to deliver the short-lived isotope, a sequence that is expensive, cumbersome and rarely available to most medical centers. Such limitations will not change significantly over the next five years and beyond.
Backscatter Ultrasound Technology
Transthoracic ultrasound technology has been used to evaluate cardiac tissue conditions, including some attempts to identify hibemating versus dead myocardium. M.R. Milunski, et al., "Ultrasonic Tissue Characterization With Integrated Backscatter," Circulation, 80:491-503 (1989). This technology is limited by the quality of the image. The ultrasound image is compromised by many factors including chest wall size, obesity and most importantly lung disease. A great majority of older patients have lung disease (e.g. chronic obstructive pulmonary disease or COPD) which significantly compromises the backscatter image quality. Many times these are the same patients who have cardiac problems as well and need evaluation. The present invention can be used in backscatter ultrasound evaluation to provide additional information about the physiological integrity of apparently dead tissue.
Without a clear transthoracic ultrasound image, current backscatter technology is somewhat limited. However, for some patients, backscatter may provide an alternative means for evaluating tissue viability. To overcome transthoracic poor image quality in many patients, echocardiography can be performed invasively by the transesophogeal approach.
Clinical Indications
There are many cardiac conditions which are life threatening and treatable, but the treatment itself is a major procedure which itself has an attendant risk to life. Cardiologists and cardiac surgeons would both benefit from a procedure which would identify cardiac tissue which has a good probability of returning to normal function. A useful assay would allow physicians to identify candidate tissue and also to select an appropriate mode of treatment.
Selected Clinical Situations that Present a Clinical Decision Dilemma and Benefit From Objective Evaluation of Viability
A. Idiopathic dilated cardiomyopathy (IDCM)
In this disease the chamber wall is hypokinetic and chamber size dilated, resembling in a sense global ischemia changes, but the chamber wall etiology may be ischemic, may be toxic, or may be idiopathic. The correct etiology cannot be determined using current methods. In IDCM both left ventricle and right ventricle have decreased levels of mitochondrial enzymes (e.g., cytochromes) and an elevated lactate dehydrogenase level due to increased anaerobic activity secondary to depressed mitochondrial function. Mild mitral regurgitation (MR) is often present in IDCM.
A prognosis of ICDM raises two dilemmas. First, when ICDM is unknown and MR is present it is difficult to distinguish if (a) left ventricular dilation is secondary to severe MR or (b) if left ventricular dilation is secondary to cardiomyopathy which causes MR. In situation (a), treatment would focus on correcting hemodynamics of MR. In situation (b), treatment would focus on correcting the etiology of cardiomyopathy, if possible. To distinguish between the two situations the tissue viability monitor is used to establish the absence or presence of cardiomyopathy. Second, in (a) patients with mild motion abnormalities and/or abnormal Q waves, the etiology may be (a) secondary to myocardial infarction due to coronary artery disease or (b) secondary to myocardial fibrosis due to severe dilated cardiomyopathy. Use of the tissue viability monitor in situation (a) may demonstrate viable but hibernating myocardium in which case angioplasty or surgery for revascularization will be essential to correct the abnormal wall motion. In situation (b), the viability monitor will show decreased amounts of viable tissue in which case surgery or angioplasty will not change the outcome and therefore are not indicated.
B. Evaluation of myocardial toxicity during chemotherapy.
C. Evaluation of types of salvageable myocardium in clinical situations that are present as cardiomyopathy.
D. Detection of myocardial rejection following transplant.
E. Evaluation of myocardial viability following bypass. In many instances there is decreased wall motion following coronary artery bypass. This may be secondary to irreversible reperfusion injury in which case there should be little expectation for recovery. In other cases the etiology of wall motion abnormality is the transient post operative stunning of an otherwise viable myocardium. In this case it is reasonable to expect recovery with improvement in due time with optimization of chemical conditions.
F. Evaluation of myocardial muscle around surgical sites before and after an operative procedure for valve repair, aneurysmectomy and repair.
Cell Mechanisms
Electron Transport Chain and the Role of NADH
The major enzymes or protein components functioning as electron-transfer components in the mitochondrial electron transport system as follows:
1. AND+-linked dehydrogenases PA1 2. Flavin-linked dehydrogenases PA1 3. Iron-sulfur proteins PA1 4. Cytochromes PA1 a) For HMO's, to approve a procedure. PA1 b) For insurance or government agencies for reimbursement. PA1 c) To medico-legally support clinical decisions.
In the following reaction the function of nicotinamide adenine dinucleotide (AND+)-linked dehydrogenases will be described as a representative of the group.
AND+-linked Dehydrogenases
The initial stage in the mitochondrial electron transport sequence consists of the generation of reducing equivalents in the tricarboxylic acid cycle (TCA), the fatty acid B-oxidation, and various other dehydrogenase reactions. The AND+-linked dehydrogenase reactions of these pathways reduce AND+to NADH while converting the reduced member of an oxidation-reduction couple to the oxidized form, for example, for the isocitrate dehydrogenase reaction. ##STR1##
Nicotinamide adeninc dinucleotide phosphate (NADP) is involved in similar reactions. In either case, once NADH or NADPH is formed in an oxidation reaction it is released from the primary dehydrogenase and serves as a substrate for the mitochondrial respiratory chain but is used in the reductive biosynthetic reactions and its level is ultimately reflected in NADH levels entering the mitochondrial respiratory chain.
The various electron-transferring proteins and other carriers of the respiratory chain are arranged in a sequential pattern in the inner mitochondrial membrane. Reducing equivalents such as NADH or flavin adeninc dinucleotide (FADH) are extracted from the TCA cycle or fatty acid .beta.-oxidation and indirectly from glycolysis and passed sequentially through the electron transport chain to make molecular oxygen. The arrangement of the mitochondrial electron transport carriers are shown in FIG. 2. In essence, electrons or reducing equivalents are fed into the electron transport chain at the level of NADH or coenzyme Q from the primary AND+-linked or FAD+-linked dehydrogenase reactions and are transported to molecular oxygen through the cytochrome chain. This electron transport system is set up so that the reduced member (XH2) of one redox couple is oxidized (X) by the next component in the system according to the direction of the arrows. For example, in the first step, ##STR2##
It should be noted that the electron transfer reactions from NADH through eoenzyme Q transfer two electrons, whereas the reactions between coenzyme Q and oxygen involving the various cytochromes are one-electron transfer reactions.
During the transfer of the electrons from the NADH / AND+couple (E0=+0.32) to molecular oxygen (E0=+0.82) there occurs an oxidation-reduction potential decrease of 1.14 V (E0=standard potential energy). These drops in potential occur in three discrete steps (site I, site II, site III in FIG. 2) as reducing equivalents or electrons are passed between the different segments of the chain. There is at least a 0.3 V decrease in the potential between each of the three coupling or phosphorylation sites. A potential drop of 0.3 V is more than sufficient to accommodate the synthesis of a high-energy phosphate bond such as occurs in ATP synthesis. When electrons enter at NADH this results in three ATP molecules generated. When electrons enter at the level of succinate through FADH this results in two ATP molecules generated. ##STR3##
Succinate is formed from the energy-rich succinyl CoA and once formed is oxidized to fumarate in the FAD-linked succinate dehydrogenase reaction of the TCA cycle. It is thought that the non-heme iron of this dehydrogenase undergoes valence changes (oxidation/reduction (Fe2+&lt;=&gt;Fe3+)) during the removal of electrons and protons from succinate and the subsequent transfer of these reducing equivalents through FAD to the mitochondrial electron-transfer chain at the coenzyme Q-cytochrome b level.
The succinate precursor succinyl CoA represents a metabolic branch point in that intermediates may enter or exit the TCA cycle at this point. Succinyl CoA may be formed from either a-ketoglutarate in the TCA cycle or from naethyl malonyl CoA, the end product of odd fatty acid chain breakdown. The metabolic fates of succinyl CoA include its conversion to succinate in the TCA cycle or entry into the porphyrin b cosynthesis pathway.
Transport of Succinate into the Mitochondria
Oxidation of succinate through the electron transport chain and its generation in the TCA cycle all occur in the mitochondria. Traffic into this matrix space is brisk but occurs largely either as active transport or as facilitated exchange or through specific proteins highly specialized for this purpose. These proteins are termed porters or translocases, most of which function in an antiport mode, i.e., a substance is assisted in moving across the membrane only in exchange for some rather specific countermoving substance of similar charge, for example ADP for ATP. No external energy supply is required for transport on a translocase (porter). At least one of the pair of transported molecules moving in the antiport (exchange) mode must be moving down a significant concentration gradient. Therefore, the translocases for a pair of substances can be driven in either direction by supplying a higher concentration of the one substance required to enter the compartment or cross the membrane. For example, when succinate is infused into the cellular matrix, it will be present at high concentration and the translocase will be driven by the concentration gradient to transport it into the mitochondria.
Effiux of a major cell constituent along a concentration gradient--whether across the mitochondrial or plasma membrane--can drive the movement of the counter substance against a gradient, thereby doing "work" until the two driving forces have been completed. For operation of the TCA cycle, only the facilitated entry of pyruvate is required. However, other porters are functional to facilitate and replicate intermediates in this cycle (see Eqn. 4, below). Malate entry from the cytosol into the mitochondria provides a source of additional reducing equivalents and makes possible a mechanism for gluconeogenesis. Citrate exit provides a means of exporting acetyl groups. The tricarboxylate carrier transports citrate, isocitrate, aconitate and such dicarboxylates as realate and succinate. ##STR4##